Within a week after the large SELECT (Selenium and Vitamin E Cancer Prevention) Trial was halted due to disappointing results (see previous posts: [1] and [2]), the negative results of yet another large vitamin trial were announced [7].
Again, no benefits were found from either vitamin C or E when it came to preventing prostate ànd other cancers.
Both trials are now prepublished in JAMA. The full text articles and the accompanying editorial are freely available [3, 4, 5].

In The Physicians’ Health Study II Randomized Controlled Trial (PHS II), researchers tested the impact of regular vitamin E and C supplements on cancer rates among 14,641 male physicians over 50: 7641 men from the PHS I study and 7000 new physicians.

The man were randomly assigned to receive vitamin E, vitamin C, or a placebo. Besides vitamin C or E, beta carotene and/or multivitamins were also tested, but beta carotene was terminated on schedule in 2003 and the multivitamin component is continuing at the recommendation of the data and safety monitoring committee.

Similar to the SELECT trial this RCT had a factorial (2×2) design with respect to the vitamins E and C [1]: randomization yielded 4 nearly equal-sized groups receiving:

400-IU synthetic {alpha}-tocopherol (vitamin E), every other day and placebo (similar to the SELECT trial)

500-mg synthetic ascorbic acid (vitamin C), daily and placebo

both active agents

both placebos.

Over 8 years, taking vitamin E had no impact at all on rates of either prostate cancer (the primary outcome for vitamin E), or cancer in general. Vitamin C had no significant effect on total cancer (primary outcome for vitamin C) and prostate cancer. Neither was there an effect of vitamin E and/or C on other site-specific cancers.
How can the negative results be explained in the light of the positive results of earlier trials?

The conditions may differ from the positive trials:

The earlier positive trials had less methodological rigor. These were either observational studies or prostate cancer was not their primary outcome (and may therefore be due to chance). (See previous post The best study design for dummies).

Clinical data suggest that the positive effect of vitamin E observed in earlier trials was limited to smokers and/or people with low basal levels of vitamin E, whereas animal models suggest that vitamin E is efficacious against high fat-promoted prostate cancer growth (20), but lacks chemopreventive effects (i.e. see [1,4] and references in [5], a preclinical study we published in 2006).
Indeed, there were very low levels of smoking in the PHS II study and the effect of the vitamins was mainly assessed on induction not on progression of prostate cancer.

Eight times higher vitamin E doses(400IE) have been used than in the ATCB study showing a benefit for vitamin E in decreasing prostate cancer risk! [1,4]

Other forms of vitamin E and selenium have been proposed to be more effective.

As Gann noted in the JAMA-editorial, the men in both recent studies were highly motivated and had good access to care. In SELECT, the majority of men were tested for PSA each year. Probably because of this intense surveillance, the mean PSA at diagnosis was low and prostate cancers were detected in an early, curable stage. Strikingly, there was only 1 death from prostate cancer in SELECT, whereas appr. 75-100 deaths were expected. There also were indications of a deficit in advanced prostate cancer in PHS II, although a much smaller one.
In other words (Gann):“how can an agent be shown to prevent serious, clinically significant prostate cancers when PSA testing may be rapidly removing those cancers from the population at risk before they progress?”

Similarly, in the SELECT trial there was no constraint on the use of other multivitamins and both studies put no restriction on the diet. Indeed the group of physicians who participated in the PHS II trial were healthier overall and ate a more nutritious diet. Therefore Dr Shao wondered“Do we really have a placebo group – people with zero exposure? None of these physicians had zero vitamin C and E” [7]. In the Netherlands we were not even able to perform a small phase II trial with certain nutrients for the simple reason that most people already took them.

What can we learn from these negative trials (the SELECT trial and this PHS II-trial)?

Previous positive results were probably due to chance. In the future a better preselection of compounds and doses in Phase 2 trials should determine which few interventions make it through the pipeline (Gann, Schroder).

Many other trials disprove the health benefits of high dose vitamins and some single vitamins may even increase risks for specific cancers, heart disease or mortality [9]. In addition vitamin C has recently been shown to interfere with cancer treatment [10].

The trials make it highly unlikely that vitamins prevent the development of prostate cancer (or other cancers) when given as a single nutrient intervention. Instead, as Dr Sasso puts it “At the end of the day this serves as a reminder that we should get back to basics: keeping your body weight in check, being physically active, not smoking and following a good diet.”

Single vitamins or high dose vitamins/antioxidants should not be advised to prevent prostate cancer (or any other cancer). Still it is very difficult to convince people not taking supplements.

Another issue is that all kind of pharmaceutical companies keep on pushing the sales of these “natural products”, selectively referring to positive results only. It is about time to regulate this.

Sources & other reading (click on grey)

Huge disappointment: Selenium and Vitamin E fail to Prevent Prostate Cancer.(post on this blog about the SELECT trial)

When I had those tired looks again, my mother in law recommended coenzyme Q, which research had proven to have wondrous effects on tiredness. Indeed many sites and magazines advocate this natural energy producing nutrient which mobilizes your mitochondria for cellular energy! Another time she asked me if I thought komkommerslank (cucumber pills for slimming) would work to loose some extra weight. She took my NO for granted.

It is often difficult to explain people that not all research is equally good, and that outcomes are not always equally “significant” (both statistically and clinically). It is even more difficult to understand “levels of evidence” and why we should even care. Pharmaceutical Industries (especially the supplement-selling ones) take advantage of this ignorance and are very successful in selling their stories and pills.

If properly conducted, the Randomized Controlled Trial (RCT) is the best study-design to examine the clinical efficacy of health interventions. An RCT is an experimental study where individuals who are similar at the beginning are randomly allocated to two or more treatment groups and the outcomes of the groups are compared after sufficient follow-up time. However an RCT may not always be feasible, because it may not be ethical or desirable to randomize people or to expose them to certain interventions.

Observational studies provide weaker empirical evidence, because the allocation of factors is not under control of the investigator, but “just happen” or are choosen (e.g. smoking). Of the observational studies, cohort studies provide stronger evidence than case control studies, because in cohort studies factors are measured before the outcome, whereas in case controls studies factors are measured after the outcome.

Most people find such a description of study types and levels of evidence too theoretical and not appealing.

Last year I was challenged to tell about how doctors search medical information (central theme = Google) for and here it comes…. “the Society of History and ICT”.

To explain the audience why it is important for clinicians to find ‘the best evidence’ and how methodological filters can be used to sift through the overwhelming amount of information in for instance PubMed, I had to introduce RCT’s and the levels of evidence. To explain it to them I used an example that stroke me when I first read about it.

I showed them the following slide :

And clarified: Beta-carotene is a vitamine in carrots and many other vegetables, but you can also buy it in pure form as pills. There is reason to believe that beta-carotene might help to prevent lung cancer in cigarette smokers. How do you think you can find out whether beta-carotene will have this effect?

Suppose you have two neighbors, both heavy smokers of the same age, both males. The neighbor who doesn’t eat much vegetables gets lung cancer, but the neighbor who eats a lot of vegetables and is fond of carrots doesn’t. Do you think this provides good evidence that beta-carotene prevents lung cancer?There is a laughter in the room, so they don’t believe in n=1 experiments/case reports. (still how many people don’t think smoking does not necessarily do any harm because “their chainsmoking father reached his nineties in good health”).
I show them the following slide with the lowest box only.

O.k. What about this study? I’ve a group of lung cancerpatients, who smoke(d) heavily. I ask them to fill in a questionnaire about their eating habits in the past and take a blood sample, and I do the same with a simlar group of smokers without cancer (controls). Analysis shows that smokers developing lung cancer eat much less beta-carotene containing vegetables and have lower bloodlevels of beta-carotene than the smokers not developing cancer. Does this mean that beta-carotene is preventing lung cancer?Humming in the audience, till one man says: “perhaps some people don’t remember exactly what they eat” and then several people object “that it is just an association” and “you do not yet know whether beta-carotene really causes this”. Right! I show the box patient-control studies.

Than consider this study design. I follow a large cohort of ‘healthy’ heavy smokers and look at their eating habits (including use of supplements) and take regular blood samples. After a long follow-up some heavy smokers develop lung cancer whereas others don’t. Now it turns out that the group that did not develop lung cancer had significantly more beta-carotene in their blood and eat larger amount of beta-carotene containing food. What do you think about that then?Now the room is a bit quiet, there is some hesitation. Then someone says: “well it is more convincing” and finally the chair says: “but it may still not be the carrots, but something else in their food or they may just have other healthy living habits (including eating carrots). Cohort-study appears on the slide (What a perfect audience!)

O.k. you’re not convinced that these study designs give conclusive evidence. How could we then establish that beta-carotene lowers the risk of lung cancer in heavy smokers? Suppose you really wanted to know, how do you set up such a study?Grinning. Someone says “by giving half of the smokers beta-carotene and the other half nothing”. “Or a placebo”, someone else says. Right! Randomized Controlled Trial is on top of the slide. And there is not much room left for another box, so we are there. I only add that the best way to do it is to do it double blinded.

Than I reveal that all this research has really been done. There have been numerous observational studies (case-control as well cohorts studies) showing a consistent negative correlation between the intake of beta-carotene and the development of lung cancer in heavy smokers. The same has been shown for vitamin E.

“Knowing that”, I asked the public: “Would you as a heavy smoker participate in a trial where you are randomly assigned to one of the following groups: 1. beta-carotene, 2. vitamin E, 3. both or 4. neither vitamin (placebo)?”

The recruitment fails. Some people say they don’t believe in supplements, others say that it would be far more effective if smokers quit smoking (laughter). Just 2 individuals said they would at least consider it. But they thought there was a snag in it and they were right. Such studies have been done, and did not give the expected positive results.
In the first large RCT (appr. 30,000 male smokers!), the ATBC Cancer Prevention Study, beta-carotene rather increased the incidence of lung cancer with 18 percent and overall mortality with 8 percent (although harmful effects faded after men stopped taking the pills). Similar results were obtained in the CARET-study, but not in a 3rd RCT, the Physician’s Health Trial, the only difference being that the latter trial was performed both with smokers ànd non-smokers.
It is now generally thought that cigarette smoke causes beta-carotene to breakdown in detrimental products, a process that can be halted by other anti-oxidants (normally present in food). Whether vitamins act positively (anti-oxidant) or negatively (pro-oxidant) depends very much on the dose and the situation and on whether there is a shortage of such supplements or not.

I found that this way of explaining study designs to well-educated layman was very effective and fun!
The take-home message is that no matter how reproducible the observational studies seem to indicate a certain effect, better evidence is obtained by randomized control trials. It also shows that scientists should be very prudent to translate observational findings directly in a particular lifestyle advice.

On the other hand, I wonder whether all hypotheses have to be tested in a costly RCT (the costs for the ATCB trial were $46 million). Shouldn’t there be very very solid grounds to start a prevention study with dietary supplements in healthy individuals ? Aren’t their any dangers? Personally I think we should be very restrictive about these chemopreventive studies. Till now most chemopreventive studies have not met the high expectations, anyway.
And what about coenzyme-Q and komkommerslank? Besides that I do not expect the evidence to be convincing, tiredness can obviously be best combated by rest and I already eat enough cucumbers…. 😉
To be continued…